Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall, et al., Curr. Opin. Immunol. 6:865-873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca2+])i, granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
There are four classes of chemokines, CXC (α), CC (β), C(γ), and CX3C (δ), depending on whether the first two cysteines are separated by a single amino acid (C—X—C), are adjacent (C—C), have a missing cysteine pair (C), or are separated by three amino acids (CX3C). The a-chemokines, such as interleukin-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-1) are chemotactic primarily for neutrophils and lymphocytes, whereas β-chemokines, such as RANTES, MIP-1α, MIP-1β, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature, 381:661-666 (1996)). The C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al., Science, 266:1395-1399 (1994)) while the CX3C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al., Nature, 385:640-644 (1997).
Chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci. 15:159-165 (1994)) which are termed “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated heterotrimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least twelve human chemokine receptors that bind or respond to β-chemokines with the following characteristic pattern: CCR1 (or “CKR-1” or “CC-CKR-1”) to MIP-1α, MIP-1β, MCP-3, RANTES (Ben-Barruch, et al., J. Biol. Chem., 270:22123-22128 (1995); Neote, et al., Cell, 72:415425 (1993)); CCR2A and CCR2B (or “CKR-2A”/“CKR-2A” or “CC-CKR-2A”/“CC-CKR2A”) to MCP-1, MCP-3, MCP-4; CCR3 (or “CKR-3” or “CC-CKR-3”) to eotaxin, RANTES, MCP; (Ponath, et al., J. Exp. Med., 183:2437-2448 (1996)); CCR4 (also referred to as “CKR4”, “CC-CKR4” or “CMKBR4”), to TARC, MDC (Imai et al. (1998) J. Biol. Chem. 273:1764-1768); CCR5 (or “CKR-5” or “CC-CKR-5”) to MIP-1α, RANTES, MIP-1β (Sanson, et al., Biochemistry, 35:3362-3367 (1996)); CCR6 to MIP-3 alpha (Greaves, et al., J. Exp. Med., 186:837-844 (1997)); CCR7 to MIP-3 beta and 6Ckine (Campbell, et al., J. Cell. Biol., 141:1053-1059(1998)); CCR8 to I-309, HHV8 vMIP-I, HFV-8 vMIP-II, MCV vMCC-I (Dairaghi, et al., J. Biol. Chem., 274:21569-21574 (1999)); CCR9 to TECK (Zaballos, et al., J. Immunol., 162:5671-5675 (1999)), D6 MIP-1 beta, RANTES, and MCP-3 (Nibbs, et al., J. Biol. Chem., 272:32078-32083 (1997)), the Duffy blood-group antigen to IL-8, Groα, RANTES, MCP-1 (Chaudhun et al. (1994) J. Biol. Chem. 269:7835-7838, Murphy et al. (2000) Pharm. Rev. 52:145-176) and CCR10 to CTACK, CCL28 (Jarmin et al. (2000) J. Immunol. 164:3460-3464, Homey et al. (2000) J. Immunol. 164:3465-3470, Wang et al. (2000) J. Biol. Chem. 275:22313-22323).
Chemokine receptors, such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX3CR1 and XCR1 have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
The CCR4 chemokine receptor, first identified by Power et al. (Power et al. (1995) J. Biol. Chem. 270:19495-19500), is expressed primarily in peripheral blood T lymphocytes. CCR4 is involved in T lymphocyte homing to the skin and lungs (see, e.g., Campbell et al. (1999) Nature 400:776-780, Gonzalo et al. (1999) J. Immunol. 163:403-411, Lloyd et al. (2000) J. Exp. Med. 191:265-273, Kawasaki et al. (2001) J. Immunol. 166:2055-2062).
The identification of compounds that modulate the function of CCR4 represents an attractive approach to the development of therapeutic agents for the treatment of inflammatory conditions and diseases associated with CCR4 activation, such as psoriasis, asthma and allergic diseases.